Sickle Cell Disease (SCD) afflicts millions of people worldwide and is associated with vaso-occlusion, ischemia, inflammation, significant morbidity, and early mortality. In SCD, abnormal polymerization of deoxygenated sickle hemoglobin (HbS) deforms the red blood cells (RBCs), changing membrane properties, increasing cellular density (mass to volume ratio), and triggering deleterious inflammation, thrombophilia, and vasculopathy. Sickle RBCs are non-deformable and adhesive in the microcirculation, particularly in parts of the body where the oxygen tension is relatively low (hypoxic), such as the kidney or spleen. Most clinical features of SCD can be traced to the polymerization of HbS and its effects on RBCs. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only currently feasible, relatively accessible, and potentially curative strategy for patients with SCD in the developed world. Gene therapy, utilizing autologous HSCT, may also address the underlying molecular cause of SCD. In addition to clinical history and conventional laboratory tests (e.g., complete blood count, reticulocyte count, hemolytic markers, and Hb composition), functional and physiologic assessments (e.g., six-minute walk test, cognitive assessments), we postulate that comprehensive Microfluidic BioChip Assays will complement assessments of efficacy in therapies of curative intent. In this Cure Sickle Cell initiative (CureSCi) project, we will assess the following key biomarkers: (1) RBC adhesion, (2) RBC deformability, (3) RBC density (mass to volume) and hemoglobin composition, and (4) blood rheology. The objectives of this CureSCi project are: Objective 1. To establish standardization and reproducibility of existing Microfluidic BioChip Assays for the clinically feasible assessment of candidate RBC biophysical biomarkers in SCD through completion of an adequately-powered multi-site patient sample acquisition plan. Objective 2. To gain broader spectrum of patient treatment and patient phenotype to achieve clinical validation of centralized Microfluidic BioChip Assays in SCD. Proposed multi-site clinical validation study includes three active and geographically distinct CureSCi project sites: UCSF Benioff Children?s Hospital Oakland (Dr. Mark Walters), Stanford Medical School (Dr. Matthew Porteus), and Emory University School of Medicine (Dr. Lakshmanan Krishnamurti). Additional sites are: Albert Einstein College of Medicine Children?s Hospital at Montefiore (Dr. Deepa Manwani), University of North Carolina School of Medicine (Dr. Jane Little), and University Hospitals Cleveland Medical Center (Dr. Lalitha Nayak). Pediatric and/or adult patients will be recruited from comprehensive SCD programs at each site, and the feasibility of multi-site processing and assay reproducibility will be confirmed, utilizing a centralized approach. The clinical validation dataset will include samples from patients at steady state and from those receiving a therapeutic agent, including patients who have had a curative therapy. Most people with SCD (99%) live in low-income countries. Our group has successfully translated and commercialized point-of-care diagnostic technologies for SCD in low-resource settings. Based on this experience, we anticipate that the Microfluidic BioChip Assays, proposed here, will be applicable to evolving patient care in both high- and low-resource settings. Proposed Microfluidic BioChip Assay technologies align well with recently announced plans from the NIH to develop cures for SCD that are applicable world-wide. Our team is committed to making Microfluidic BioChip Assays available for translation on global scale, including in low-resource settings.